Method for separation of racemic compound-forming chiral substances by a cyclic crystallization process and a crystallization device

ABSTRACT

The invention concerns a method for separating a racemic compound-forming chiral substance by a cyclic crystallization process which is conducted in at least one first crystallization unit ( 10 ) and in at least one second crystallization unit ( 18 ), wherein in a first process cycle an enantiomer is crystallized in the first crystallization unit ( 10 ) and a racemic compound is crystallized in the second crystallization unit ( 18 ), wherein in a second process cycle the enantiomer is crystallized in the second crystallization unit ( 18 ) and the racemic compound is crystallized in the first crystallization unit ( 10 ), wherein during each process cycle in at least one process sub-step (B→C, F→G) a mother liquor ( 12 ) being contained in the first crystallization unit ( 10 ) is mutually exchanged with a mother liquor ( 20 ) being contained in the second crystallization unit ( 18 ). An auto-seeding process sub-step is applied at the beginning of a process cycle.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority from PCT/EP2010/062682,filed Aug. 31, 2010, which claimed the benefit of priority from EuropeanPatent Application No. 09 169 202.0, filed Sep. 2, 2009, each of whichis hereby incorporated by reference in its entirety.

DESCRIPTION

The present invention relates to a method for separation ofcompound-forming chiral substances by a cyclic crystallisation process,which is conducted in at least one first and in at least one secondcrystallization unit, wherein in a first process cycle an enantiomer iscrystallized in the first crystallization unit and a racemic compound iscrystallized in the second crystallization unit.

Chiral substances are optical active molecules which have the ability torotate plane-polarized light. These molecules exist in two differentstereoisomeric forms which are non-super-imposable mirror images of eachother and are so-called enantiomers and counter-enantiomers. These twotypes of enantiomers have identical chemical and physical properties butoften have different effects on biological entities.

A mixture of an equimolar composition of enantiomers andcounter-enantiomers is called a racemate while racemic compounds areavailable in a crystal structure with an equimolar composition ofoptical active enantiomers and counter-enantiomers in an ordered ratiowithin the elementary cell.

In pharmaceutical, agrochemical and allied industries there is a growingdemand for chiral molecules for processing drugs, food and fragrance,especially for those enantiomers, which have the desired properties. Inparticular the separation of pure enantiomers from racemic compounds hasa high economic potential since the majority of available chiralsubstances is existent as racemic compound. However in comparison toconglomerate systems, mixtures of compound-forming systems reveal anadditional stable solid phase in their solubility characteristics, whichinhibits the possibility for a direct crystallization, i.e. to obtainboth enantiomers at the same time.

The enantioselective separation of racemic compound-forming mixtures isknown from the state of the art. A generally recognized method forseparation of racemic compounds is the preferential crystallizationwhich can be applied to selectively obtain the desired enantiomer. Arequired starting point for application of a preferentialcrystallization to obtain a desired pure enantiomer and/or a racemiccompound as a by-product is basically a saturated solution, which isenriched with the desired enantiomer.

WO 2007/023129 A2 relates to a hybrid method for the cycliccrystallization of enantiomers from compound-forming systems in onecrystallization unit, i.e. a batch-wise mode. Based on an initialenrichment process step to provide a mixture with a certain enantiomericexcess close to the eutectic composition, preferential crystallizationis applied. The solution then is supersaturated by cooling down thetemperature and afterwards seeded with crystals of the desiredenantiomer, which initializes the crystallization of the desired pureenantiomer. After gaining the solid enantiomer by filtration andaddition of fresh feed, the clear supersaturated solution is seeded withcrystals of the racemic compound and the racemic compound as aby-product is crystallized. The enantiomer and the racemic compound areproduced alternatingly and successively in one crystallization unit.Therefore the productivity of this process is limited since only inevery second cycle the desired pure enantiomer can be obtained.

In addition the concentration of the desired species in the motherliquor, i.e. in the liquid phase, is typically decreasing during thisbatch wise operated process, since the quantity of crystallizedenantiomers or racemic compound is more and more increasing, while theconcentration of the opposite species does not change. Consequently, thedriving force (supersaturation) for the crystallization decreases withthe progress of the process while there is an increasing tendency ofnucleation of the counter-species, which has also a negative impact onproductivity of the process and on yield, purity and quality of thefinal product. Furthermore separately produced seed crystals need to beadded after each restart of the process cycle to initialize anothercrystallization cycle.

It is therefore an object of the present invention to provide a methodfor an efficient separation of enantiomers of a racemic compound-formingchiral substance while improving the disadvantages known from the stateof the art and which is itself a simple and inexpensive method.

Another object is to provide a universal applicable method for anefficient production of a desired enantiomer while the productivity,yield and purity is increased and while an auto-seeding techniqueeliminates the problems connected with a separate seed addition.

A further object of the present invention is to provide acrystallization device for application of a method according to thepresent invention, with at least two crystallization units, which arecoupled via liquid phases by mutual exchange of mother liquors.

According to the invention, this is achieved by a method and a deviceaccording to the independent claims. Further embodiments of theinvention are subject matter of the dependent claims.

The invention concerns a method for a cyclic separation of acompound-forming substance, while the technique of preferentialcrystallization is applied. The inventive method starts up from at leasttwo crystallization units which are hydraulically coupled. With thedefinition of a crystallization unit, e.g. a container, a tank, areactor or a further vessel might be supposed, which is intended toreceive a liquid mixture, a liquid phase or a suspension.

The hydraulically coupling of the above mentioned two crystallizationunits is realized for example by means of supply pipes and which arehydraulically connecting the interior of both crystallization units forthe intended exchange of a liquid.

The liquid phases in both crystallization units are mutually, exchangedfor example by means of two pumps or by means of the force of gravity.The so-called mother liquor of the first crystallization unit istransferred to the second crystallization unit, while the mother liquorof the second crystallization unit is transferred to the firstcrystallization unit. Thereby the liquid phase is exchanged at a certainor infinitely high rate.

The advantage of the exchange of the liquid phases in bothcrystallization units can be explained from a thermodynamic point ofview. In the uncoupled case, the concentration of the desired species,which are intended to be crystallized in the mother liquor, in generalis decreasing when the crystallization process is in progress, while theconcentration of the counter-species remains constant.

As explained above, the degree of supersaturation in the mother liquoris the driving force for crystallization, i.e. the crystallization rateis in the uncoupled case permanently decreasing.

However, when at least two crystallization units are advantageouslycoupled with each other, the concentration of the respectivecounter-species is permanently decreased. Thus the probability for anucleation of the undesired opposite species is notable reduced.Contrary, compared to the uncoupled case, the concentration of thedesired species in the mother liquor is increased. Thus the coupling oftwo crystallization units leads to a higher crystallization rate, ahigher productivity and product mass.

Preferably the method according to the invention comprises a separate ora parallel crystallization process of the desired enantiomer and theracemic compound in the at least two crystallization units. It has to benoted that a simultaneous or a non-simultaneous operation mode of the atleast two crystallization units is possible.

For example the crystallization process in the first crystallizationunit is started previously before the crystallization process in thesecond crystallization unit is started, i.e. is operated time-shifted.Imaginable is also a partly simultaneous operation mode, whereby forexample a process sub-step of a crystallization processes is initializedin the second crystallization unit, when another process sub-step in thefirst crystallization unit is finished or has reached a certaincondition.

In a preferred method the process cycle is operated several times, i.e.in a cyclic and/or in a continuous manner, while in each of the bothcrystallization units the enantiomer and the racemic compound iscrystallized in an alternating manner.

Preferably the process according to the invention may be repetitivelyoperated without the necessity to separately introduce seed crystals toinitiate a subsequent crystallization process. In addition thecrystallization can be performed as a cooling crystallization, i.e. thetemperature of the mother liquor is decreased continuously during thecrystallization process in order to optimally affect the degree ofsupersaturation which results in a higher crystallization rate.

In a preferred embodiment of the claimed method the two or more separatecrystallization units are coupled via the liquid phase when thecrystallization process is operated in proximity to the eutecticcomposition. Therefore the probability of the risk for a nucleation ofthe respective counter-species is reduced, while the purity isincreased.

It is possible and desirable to use exchange flow-rates adjusted to thespecific crystallization process occurring in the two crystallizationunits. This might be realized by an on-line or an off-line measurementof the physical and chemical conditions in the mother liquors andcontrolled by a process parameter. For example the enantiomeric excessin the first crystallization unit and/or in the second crystallizationunit is monitored, while the exchange flow rates of the mother liquorsis adapted accordingly to a certain rate.

In a further preferred embodiment of the claimed method a so-calledentrainment process sub-step, wherein the exchange of mother liquors isinterrupted, advantageously enriches the mother liquors with therespective counter species in each crystallization unit. This enrichmentis advantageously used to generate the desired seed crystals for theinitialization of a subsequent crystallization process cycle.

In a preferred embodiment of the invention a so-called auto-seedingprocess sub-step is comprised. After the feeding with eutectic feedmaterial to the crystallization units to generate new initial suspensionfor the crystallization process sub-steps, during the auto-seedingprocess sub-step the temperature of the mother liquor is increased inorder to selectively dissolve the opposite species, while the desiredseed crystals remain present in the suspension. In addition, the motherliquor then is tempered to a certain temperature in order to ensure theequilibrium condition, i.e. just pure crystals of the desired speciesremain in the mother liquor.

In a preferred embodiment of the method, the process comprises severalprocess sub-steps which can be operated repetitively in a closed processcycle and which are performed in a successive sequence in each of theboth crystallization units separately. An individual operation order orthe omission of at least one of the described process sub-steps ispossible, but might lead to a sub-optimal operation of the process.

Further advantages and embodiments will be demonstrated by the encloseddrawings:

FIG. 1 schematically illustrates the crystallization device with twocrystallization units according to the invention;

FIG. 2 shows a ternary phase diagram with 6 different phase areas forthe racemic compound-forming system;

FIG. 3 shows the relevant crystallization trajectories in a ternaryphase diagram according to the invention;

FIG. 4 shows a theoretical temperature profile for a process accordingto the invention;

FIG. 5 shows the temperature and concentration profile incrystallization unit 10 and 18 as function of time for an exampleprocess, i.e. the mandelic acid/water system;

FIG. 6 shows the concentration profile of S- and racemic mandelic acidin crystallization unit 10 and 18 as a function of the temperature.

FIG. 7 shows the enantiomeric excess as a function of the time for anexample process, i.e. the mandelic acid/water system;

FIG. 1 shows the crystallization device with two crystallization units10,18, which are coupled via the liquid phase. The first crystallizationunit 10 and the second crystallization unit 18 are connected with eachother via exchange pipes 16, 17. The first crystallization unit (10) isfilled with the mother liquor (12) and the second crystallization unitis filled with the mother liquor (20). To guarantee the exchange ofsolid-free mother liquor from one crystallization unit to the othercrystallization unit, each crystallization unit is equipped with aninternal filter unit (19).

To obtain a thorough mixing each crystallization unit is equipped with astirrer (13) and a driving unit (14). To ensure a rapid cooling-down andheating-up of the mother liquor, during polythermal operation mode, bothcrystallization units are equipped with a cooling-/heating-jacket (11),which is supplied by a liquid heat transfer medium.

A crystallization-based separation process is most suitable to bedemonstrated in a ternary phase diagram which characterizes thedifferent solid/liquid phases of a ternary substance system. FIG. 2shows schematically the ternary solubility phase diagram of twoenantiomers (+)-E and (−)-E for a racemic compound-forming system and asolvent S. The dashed lines, which run from the binary eutecticcompositions Eut to the top corner point S of the triangular diagramrepresent the so-called eutectic lines 23. Reference Rac on the bottomedge of the diagram denotes the racemic composition. The solubilityisotherm 29 has five distinctive points (enantiomers, racemic compoundand 2 eutectic points). Compound-forming substance systems arecharacterized in that an intermediate racemic compound is formed andtherefore the area below the solubility isotherm is divided into fivephase areas. Three two-phase regions and two three-phase regions existbelow the solubility isotherm.

In the three two-phase regions 24, 25, 26, stable solid phases of the(+)-E enantiomer in region 24, the (−)-E enantiomer in region 25 or theracemic compound in region 26 are in equilibrium with the correspondingsaturated liquid phases.

In the two three-phase regions 21 the enantiomers (+)-E or (−)-E and theracemic compound coexist while the enantiomer (+)-E or (−)-E and theracemic compound as solid phases are in equilibrium with a saturatedliquid of eutectic composition.

To separate either the (+)-E or the (−)-E enantiomer from a racemiccompound the two three-phase regions 21 of the ternary phase diagramsare interesting and applied for the method of preferentialcrystallization according to this invention.

The following described theoretical separation process cycle isexemplarily described on the (+)-E-side of the ternary phase diagram(FIG. 3), whereas the separation process can be applied on the(−)-E-side of the diagram accordingly to gain the (−)-E enantiomer.

FIG. 3 b shows a detailed view of the relevant process trajectoriesshown in FIG. 3, which are described below.

The theoretical temperature profile of the described process is shown inFIG. 4.

To start-up the process according to the preferred method of theinvention, enriched quasi-eutectic material is feeded into bothcrystallization units 10, 18. Super-eutectic material, i.e. a mixturehaving a composition on the enantiomer side of the eutectic line, isfeeded in crystallization unit 10 and sub-eutectic material, i.e. amixture having a composition on the racemic compound side of theeutectic line, is feeded in crystallization unit 18 and is tempered at atemperature T (susp) together with the solvent. As a consequence, incrystallization unit 10 (+)-E-enantiomer crystals are present and incrystallization unit 18 crystals of the racemic compound are present(points A*/A and E*/E in FIG. 3 b and FIG. 4). These crystals are usedas seed crystals.

The so-called auto-seeding step is executed between the trajectorypoints A*→A and E*→E in both crystallization units (10,18) accordingly.At the start-up of such a cyclic process alternatively one can startwith eutectic mixtures and once add seeds of (+)-E in crystallizationunit 10 and racemic compound crystals in crystallization unit 18 toinitialize the process cycle for the very first time, while thesuccessive process cycles are self-seeded by the auto-seeding processsub-step.

During this auto-seeding step the not desired counter-species areselectively dissolved by tempering the suspension to a certaintemperature limit T (susp) which is below the saturation temperaturelimit T (sat). Thus the seed crystals of the desired species aregenerated in the crystallization units (10,18) and the starting points Aand E are reached.

The temperature of both suspensions then is reduced at a certain coolingrate and the crystallization process is started due to thesupersaturation (FIG. 4). Racemic compound crystallizes incrystallization unit 18 according to the theoretical crystallizationtrajectory A→B. (+)-E crystallizes accordingly in crystallization unit10 (point E→F). After exceeding the eutectic line (point B and F), themutually exchange of the liquid mother liquors is started at a certainexchange rate (point B→C and F→G), which results in a reduction of thesupersaturation of the respective counter-species in the mother liquorswhile the crystallization rate of the desired species is increased. Thenthe selective crystallization process is operated under optimalconditions, in proximity to the eutectic line.

At points C and G the mutual exchange of the mother liquors is stoppedand the crystallization processes are continued by a so-calledentrainment step in both crystallization units (10,18). As a result,besides to the crystallization of the desired (+)-E-enantiomer incrystallization unit 10 and of the racemic compound in thecrystallization unit 18, the mother liquor enriches with the respectivecounter-species. At points D and H both crystallization processes arestopped and the solid end products are gained from both crystallizationunits (10,18). The mother liquor 12 in the first crystallization unit 10is enriched with racemic compound and the mother liquor (20) in thesecond crystallization unit 18 is enriched with enantiomer. New eutecticfeed is added to both mother liquors in crystallization unit 10 and 18and the starting points A* and E* (or A and E) are reached again. Now incrystallization unit 10 racemic compound and in crystallization unit 18pure (+)-E enantiomer is gained in the next process cycle.

The following example process refers to the separation of racemicmandelic acid from a liquid aqueous solution whereas the desired targetenantiomer is (+S)-mandelic acid. Of course the method according to theinvention can be applied to further compound-forming substance systems,too. Novel application fields of the invention are further substanceswith eutectic characteristics like Alanin, Valin, Ibuprofen,Nitrendipin, Pseudoephedrin, Atenolol.

Both crystallization units are operated simultaneously. The experimentis started by preparation of differently enriched quasi-eutectic aqueousmixtures. Crystallization unit 10 is feeded with 300 g of ansuper-eutectic mixture of S-mandelic acid and racemic mandelic acid andcrystallization unit 18 is feeded with 300 g of a sub-eutectic mixtureof racemic mandelic acid and (S)-mandelic acid. The initial enantiomericexcess [ee] for the S-mandelic acid and

racemic mandelic acid were set to ee=42% and ee=38% while the eutecticcomposition has an enantiomeric excess of ee=40%.

The internal conditions in both crystallization units are depicted inFIG. 5. The measured temperature profiles 50 and the trend of therefraction index 51 indicates the degree of supersaturation in thesolution over the process course NE C/G in both crystallization units.

Both mixtures are initially tempered at 21° C. (before time zero in FIG.5) while the respective counter-species are selectively dissolved togenerate a sufficient excess of the desired seed crystals. The startingpoints A and E are reached. At that time the mixtures are cooled downsuccessively in both crystallization units (10,18) at a cooling rate of0.1° C./min (point A→C, E→G).

S-mandelic acid crystallizes in first crystallization unit 10 whileracemic mandelic acid is crystallized in second crystallization unit 18.At a temperature of about 20° C. both mother liquors have an eutecticcomposition of the enantiomers (intersection point of trajectories ABand EF in FIG. 3). During the cooling phase S-mandelic acid and racemicmandelic acid are crystallizing continuously in the crystallizationunits 10 and 18.

When the exchange of the mother liquors is initialized (points B and Fat a temperature of about 19° C. after about 20 minutes) the kinetics ofthe crystallization is improved, what can be clearly identified by thechange of the slope in the concentration profile. The crystallizationrate is increased and also stable until the process sub-step isinterrupted at points G and C at a temperature of about 11° C.

FIG. 6 demonstrates the concentrations of the S-mandelic acid andracemic mandelic acid during the crystallization in both crystallizationunits with reference to the eutectic composition. It can be seen thatthe concentration course of both species follows the eutectic line withonly moderate supersaturations, also with reference to the respectivecounter-species.

FIG. 7 characterizes the enantiomeric excess of the process courseduring the steps B→D and F→H for the racemic compound and the(S)-enantiomer of mandelic acid in a further experiment. Initially theenantiomeric excess is kept stable corresponding to eutectic compositionin both crystallization units. When the exchange of mother liquors isstopped after 70 minutes (point C/G) the entrainment step issubsequently executed, i.e. the counter-species are enriched in themother liquors. While the enantiomeric excess is decreasing, S-mandelicacid is further on crystallizing in crystallization unit 10 and racemicmandelic acid is further on crystallizing in crystallization unit 18while the enantiomeric excess is increasing. The process is stopped atpoints D and H and the gained products are filtered off.

The purity of the gained (S)-enantiomer and the racemic compound ofmandelic acid were more than 96% and more than 99% respectively. Thefinal solid products are obtained with about 25 g of racemic compoundand about 17 g of S-mandelic acid which corresponds to a yield of 4% forracemic compound and 3% for S-mandelic acid.

The mother liquors of both crystallization units contained therespective counter-species with an enantiomeric excess of ee=6 to 7%.

By feeding both crystallization units with new eutectic material asubsequent cycle once more can be initiated by an in-situ generation ofseed crystals by another auto-seeding process step.

The research of the applicant has shown that the method of a cyclicseparation of a racemic compound-forming chiral substance system bymeans of an auto-seeded simultaneous preferential operation is feasibleand provides stable process conditions.

The invention according to the invention offers a safe process regimewith only moderate supersaturations of the undesired counter-species,since the process is conducted close to the eutectic equilibrium. By theexchange of mother liquors the nucleation of the respective undesiredspecies can be avoided. Therefore a method is provided, to producehigh-qualitative products with respective high purity and yield whilethe productivity is increased. When the method is performed in amultiple cycle, i.e. when several process cycles are performedsuccessively, no further adding of seed crystal seeds is required.

LIST OF REFERENCES

-   10 First crystallization unit-   11 Cooling-/heating-jacket-   12 Mother liquor, crystallization unit-   13 Stirrer-   14 Motor/driving unit-   15 Lid-   16 Exchange pipe, second crystallization unit-   17 Exchange pipe, first crystallization unit-   18 Second crystallization unit    -   19 Filter unit    -   20 Mother liquor, second crystallization unit    -   21 Three-phase areas, ((+/−)E enantiomer and racemic compound)-   23 Eutectic line-   24 Two-phase area, (+)-E enantiomer-   25 Two-phase area, (−)-E enantiomer-   26 Two-phase area, racemic compound-   28 Eutectic point-   29 Solubility isotherm-   31 Metastable solubility line-   50 Temperature profile, first and second crystallization unit-   51 Refraction index, first and second crystallization unit-   63 Saturation line eutectic composition of the enantiomers-   A*, E* Process start points-   A,B,C,D Process points of racemic compound crystallization-   E,F,G,H Process points of enantiomer crystallization-   ee enantiomeric excess [−]-   Rac Racemat-   S Solvent-   T (susp) Temperature of suspension-   T (sat) Temperature of saturation-   T (end) Temperature at end of crystallization

1. A method for separating a racemic compound-forming chiral substancecomprising a cyclic crystallization process which is conducted in atleast one first crystallization unit and in at least one secondcrystallization unit, wherein in a first process cycle an enantiomer iscrystallized in the first crystallization unit and a racemic compound iscrystallized in the second crystallization unit, wherein in a secondprocess cycle the enantiomer is crystallized in the secondcrystallization unit and the racemic compound is crystallized in thefirst crystallization unit, wherein during each process cycle in atleast one process sub-step a mother liquor in the first crystallizationunit is mutually exchanged with a mother liquor in the secondcrystallization unit.
 2. The method according to claim 1, wherein thecyclic crystallization process conducted in the first crystallizationunit and the cyclic crystallization process conducted in the secondcrystallization unit are operated simultaneously.
 3. The methodaccording to claim 1, wherein the cyclic crystallization processconducted in the first crystallization unit and the cycliccrystallization process conducted in the second crystallization unit areoperated non-simultaneously.
 4. The method according to claim 1, whereinthe temperature of the mother liquor in the first crystallization unitand/or the second crystallization unit is reduced during at least onecrystallization process sub-step.
 5. The method according to claim 1,wherein a continuous mutual exchange of the mother liquors between thefirst crystallization unit and the second crystallization unit iscarried out.
 6. The method according to claim 1, wherein a discontinuousmutual exchange of the mother liquors between the first crystallizationunit and the second crystallization unit is carried out.
 7. The methodaccording to claim 5, wherein the mutual exchange of the mother liquorsbetween the first crystallization unit and the second crystallizationunit is carried out by a varying exchange flow rate.
 8. The methodaccording to claim 7, wherein the exchange flow rate is controlled by aprocess parameter, measured in at least one of the mother liquors. 9.The method according to claim 1, wherein the process sub-step of themutual exchange of the mother liquors between the first crystallizationunit and the second crystallization unit is carried out when anenantiomeric excess (ee) in the mother liquors of the firstcrystallization unit and/or the second crystallization unit is inproximity to an eutectic composition.
 10. The method according to claim1, further comprising an auto-seeding process sub-step, wherein theenantiomer or the racemic compound is selectively dissolved while thetemperature in the first crystallization unit and/or the secondcrystallization unit is increased to a certain temperature T(susp),wherein seeds of the desired enantiomer or of the desired racemiccompound will remain not dissolved.
 11. The method according to claim10, further comprising at least one entrainment process sub-step carriedout to establish an eutectic composition in the mother liquor of thefirst crystallization unit and/or the second crystallization unit,wherein no mutual exchange of the mother liquors between the firstcrystallization unit and the second crystallization unit is carried out.12. The method according to claim 11, wherein the entrainment processsub-step is carried out after the auto-seeding process sub-step.
 13. Themethod according to claim 1, further comprising at least one entrainmentprocess sub-step carried out to enrich the mother liquors with theenantiomer or the racemic compound and to increase the amount ofcrystallized enantiomer or of the racemic compound, wherein no mutualexchange of the mother liquors between the first crystallization unitand the second crystallization unit is carried out.
 14. The methodaccording to claim 13, wherein the entrainment process sub-step iscarried out after the process sub-step of the mutual exchange of themother liquor between the first crystallization unit and the secondcrystallization unit.
 15. The method according to claim 13, furthercomprising at least one feeding process sub-step, wherein eutecticfeeding material is introduced in the first crystallization unit and/orthe second crystallization unit.
 16. The method according to claim 15,wherein the feeding process sub-step is carried out after theentrainment process sub-step.
 17. A crystallization device forapplication of a method according to claim 1, wherein at least twocrystallization units are coupled via liquid phases by mutual exchangeof mother liquors.
 18. The method according to claim 6, wherein themutual exchange of the mother liquors between the first crystallizationunit and the second crystallization unit is carried out by a varyingexchange flow rate.
 19. The method according to claim 18, wherein theexchange flow rate is controlled by a process parameter, measured in atleast one of the mother liquors.
 20. The method according to claim 1,wherein the process sub-step of the mutual exchange of the motherliquors between the first crystallization unit and the secondcrystallization unit is carried out when an enantiomeric excess (ee) inthe mother liquor of the first crystallization unit and/or the secondcrystallization unit is within a range of +/−10 mass-% to the eutecticcomposition.
 21. The method according to claim 1, wherein the processsub-step of the mutual exchange of the mother liquors between the firstcrystallization unit and the second crystallization unit is carried outwhen an enantiomeric excess (ee) in the mother liquor of the firstcrystallization unit and/or the second crystallization unit is within arange of +/−5 mass-% to the eutectic composition.
 22. The methodaccording to claim 1, wherein the process sub-step of the mutualexchange of the mother liquors between the first crystallization unitand the second crystallization unit is carried out when an enantiomericexcess (ee) in the mother liquor of the first crystallization unitand/or the second crystallization unit is within a range of +/−2 mass-%to the eutectic composition.